Inflammatory bowel disease (IBD), including Crohn?s disease and ulcerative colitis, affects 1-2 million people in the United States, and is a significant financial burden for the country. IBD increases the risk factor for other diseases such as colorectal cancer and atherosclerosis. Intestinal epithelial cells (IECs) form the physical barrier that protects the body from the hostile environment of the gut, and damage to the intestinal epithelium leads to the entry of noxious molecules and organisms, which activates the mucosal immunity. Lysophosphatidic acid (LPA), a naturally occurring bioactive lipid, acts on a family of G protein-coupled receptors to mediate multiple effects that can regulate survival and proliferation of various cell types. Of six known LPA receptors, LPA5R is highly expressed in the gastrointestinal (GI) tract. A recent genome-wide association study (GWAS) for early on- set of IBD identified a single nucleotide polymorphism within the GPCR GPR35. A subsequent study has shown that LPA is an endogenous ligand of GPR35, linking aberrant LPA-mediated signaling to the pathogenesis of IBD. Significant expression of LPA5R in the GI tract and the suggestion of aberrant LPA-mediated signaling prompted us to generate a novel mouse model in which LPA5R can be deleted inducibly or constitutively. Preliminary studies show that inducible deletion of LPA5R resulted in crypt IEC apoptosis, severe colitis, and increased morbidity, without visible effects on villus IECs. In contrast, mice with constitutive deletion of LPA5R appear normal, suggesting compensatory protection. Surprisingly, we found that crypt epithelial cells with constitutive deletion of LPA5R are more resistant to ionizing radiation- or cytokine-induced apoptosis, suggesting overcompensated cell survival. However, both constitutive and inducible deletion resulted in increased epithelial permeability and decreased epithelial junctional protein expression in villus epithelium, suggesting that LPA5R regulates epithelial barrier function. We hypothesize that LPA5R maintains the integrity of intestinal epithelium by regulating survival of crypt epithelial cells and the epithelial barrier functions at the brush border. We will investigate the underlying cause of IEC death upon LPA5R deletion and the role of LPA5R in IEC regeneration (aim 1). We will determine the underlying mechanism for the compensatory increase in IEC survival in constitutive deletion and test the hypothesis that overcompensated crypt cell survival promotes survival of abnormal cells in response to stress (aim 2). Additionally, we will investigate that epithelial barrier dysfunction in the absence of LPA5R that elevates intestinal inflammation and, together with increased IEC survival, increases the susceptibility to colon neoplasia (aim 3). The proposed studies should reveal the novel functions of LPA5R in the maintenance of intestinal epithelium. We anticipate that successful completion of this study will identify LPA5R as a key regulator of epithelial repair and colonic neoplasia, and the findings generated from these studies will have significant translational potential that may eventually be extended to human disease in the future.